Porcine circovirus (PCV) is a group of four single-stranded DNA viruses that are non-enveloped with an unsegmented circular genome. They are members of the genus '' Circovirus'' that can infect

pig The pig (''Sus domesticus''), often called swine, hog, or domestic pig when distinguishing from other members of the genus '' Sus'', is an omnivorous, domesticated, even-toed, hoofed mammal. It is variously considered a subspecies of ''Sus ...

s. The viral capsid is icosahedral and approximately 17 nm in diameter. PCVs are the smallest viruses replicating autonomously in

eukaryotic Eukaryotes () are organisms whose Cell (biology), cells have a cell nucleus, nucleus. All animals, plants, fungi, and many unicellular organisms, are Eukaryotes. They belong to the group of organisms Eukaryota or Eukarya, which is one of the ...

cells. They replicate in the nucleus of infected cells, using the host polymerase for genome amplification. PCV-2 causes Porcine circovirus associated disease or postweaning multisystemic wasting syndrome (PMWS). An effective vaccination is now available. Fort Dodge Animal Health (

Wyeth Wyeth, LLC was an American pharmaceutical company. The company was founded in Philadelphia, Pennsylvania, in 1860 as ''John Wyeth and Brother''. It was later known, in the early 1930s, as American Home Products, before being renamed to Wyeth in ...

) launched the first

USDA The United States Department of Agriculture (USDA) is the federal executive department responsible for developing and executing federal laws related to farming, forestry, rural economic development, and food. It aims to meet the needs of com ...

approved vaccine in 2006, containing an inactivated virus (

ATCvet The Anatomical Therapeutic Chemical (ATC) Classification System is a drug classification system that classifies the active ingredients of drugs according to the organ or system on which they act and their therapeutic, pharmacological and chemical ...

code: ).

Classification

Three strains of PCV are known as of 2018: * PCV-1 (first identified in 1974) readily infects, but is not known to cause disease in swine. * PCV-2 (first isolated in 1997) causes PMWS, which over time results in significant depletion of lymphocytes; postmortem examination of diseased animals reveals enlarged

lymph nodes A lymph node, or lymph gland, is a kidney-shaped organ of the lymphatic system and the adaptive immune system. A large number of lymph nodes are linked throughout the body by the lymphatic vessels. They are major sites of lymphocytes that inclu ...

and abnormal lung tissue. However, viral infection by itself tends to cause only mild disease, and co-factors such as other infections or immunostimulation seem necessary for development of severe disease. For example, concurrent infection with porcine parvovirus or PRRS virus, or immunostimulation lead to increased replication of PCV-2 and more severe disease in PCV-2-infected pigs. * PCV-3 (first described in 2015) causes a wide range of problems, and may be widespread among pigs. PCV-1 and PCV-2 show a high degree of sequence identity and a similar genomic organisation; nevertheless, the basis of the distinct pathogenicity has not yet been unravelled. The organization for PCV-3 is similar, but the sequence identity is much lower.

Genome

PCV's genome is one of the simplest of all viruses, requiring only a

capsid A capsid is the protein shell of a virus, enclosing its genetic material. It consists of several oligomeric (repeating) structural subunits made of protein called protomers. The observable 3-dimensional morphological subunits, which may or ma ...

protein (ORF2) and two replicase proteins (ORF1) in order to replicate and produce a functional virus. Due to the simplicity of PCV, it must rely heavily on the host's cellular machinery to replicate. The origin of replication is located on a small octanucleotide stem-loop that is flanked by

palindromic A palindrome is a word, number, phrase, or other sequence of symbols that reads the same backwards as forwards, such as the words ''madam'' or ''racecar'', the date and time ''11/11/11 11:11,'' and the sentence: "A man, a plan, a canal – Pana ...

repeats, with the ORF's being located head-to-head on both sides of the Ori. Specifically, ORF1 is located clockwise and ORF2 is located counterclockwise of the Ori. The two replicase enzymes that are created from ORF1, Rep and Rep', are conserved between the two types of PCV, and are part of the early phase of the virus. The replicases differ in that Rep is the full ORF1 transcript of 312 amino acids, whereas Rep' is a truncated form of ORF1 as a result of splicing and is only 168 amino acids in length. The promoter for rep (Prep) contains an Interferon-Stimulated Response Element (ISRE) that suggests Rep and Rep' are regulated by

cytokine Cytokines are a broad and loose category of small proteins (~5–25 kDa) important in cell signaling. Cytokines are peptides and cannot cross the lipid bilayer of cells to enter the cytoplasm. Cytokines have been shown to be involved in autocrin ...

involvement, and is probably a means for the virus to overcome the host's immune responses to infection. Rep and Rep' form a

dimer Dimer may refer to: * Dimer (chemistry), a chemical structure formed from two similar sub-units ** Protein dimer, a protein quaternary structure ** d-dimer * Dimer model, an item in statistical mechanics, based on ''domino tiling'' * Julius Dimer ...

that binds to two

hexameric In chemistry and biochemistry, an oligomer () is a molecule that consists of a few repeating units which could be derived, actually or conceptually, from smaller molecules, monomers.Quote: ''Oligomer molecule: A molecule of intermediate relati ...

regions adjacent to the stem-loop, H1 and H2, which is required for replication. When the dimer binds to this region, the replicases cleave the loop region of the stem-loop and remain covalently bound to the H1 and H2 regions of the DNA, which becomes the 5' end of the DNA. The newly formed 3'OH end forms a primer using host RNA polymerase, which is then used by the host's

DNA polymerase A DNA polymerase is a member of a family of enzymes that catalyze the synthesis of DNA molecules from nucleoside triphosphates, the molecular precursors of DNA. These enzymes are essential for DNA replication and usually work in groups to create ...

to begin transcription of the viral DNA via

rolling circle replication Rolling circle replication (RCR) is a process of unidirectional nucleic acid replication that can rapidly synthesize multiple copies of circular molecules of DNA or RNA, such as plasmids, the genomes of bacteriophages, and the circular RNA ...

. After the complementary DNA strand has been created, the stem region of the stem-loop forms a loose, non-hydrogen bonded, quadruplet DNA structure. This loosely associated structure can form short lived DNA-trimers which forms two templates for replication, as well as maintaining the nucleic integrity of the stem region of the stem-loop. The termination of the replication sequence has not been identified, yet, though there is evidence supporting that Rep also represses its own promoter, Prep. The ORF2 region encodes the capside protein Cap (aka CP), which differs slightly between PCV-1 and PCV-2. This variation within PCV may explain why PCV-1 is non-pathogenic, while PCV-2 is pathogenic. The promoter for this protein is located within ORF1, within the site where Rep' is truncated, and is splice from the same exon to the starting point of the ORF2 coding region and expressed during both early and late phases. This is the

immunogenic Immunogenicity is the ability of a foreign substance, such as an antigen, to provoke an immune response in the body of a human or other animal. It may be wanted or unwanted: * Wanted immunogenicity typically relates to vaccines, where the injectio ...

region of the virus and is the primary area of research for creating a vaccine to treat PMWS. There is a third gene encoded in the opposite orientation to ORF1 in the genome. This gene is transcribed and is an essential gene involved in viral replication.He JL, Dai D, Zhou N, Zhou JY (2012) Analysis of Putative ORF3 Gene Within Porcine Circovirus Type 2. Hybridoma (Larchmt) 31(3):180-187

Size

Porcine circovirus is a replicating entity with one of the smallest DNA strands consisting of a simple loop of DNA. The DNA sequence for Porcine circovirus type 2 strain MLP-22 is 1726 base pairs long.

Entry

PCV infects a wide variety of cell types, including

hepatocytes A hepatocyte is a cell of the main parenchymal tissue of the liver. Hepatocytes make up 80% of the liver's mass. These cells are involved in: * Protein synthesis * Protein storage * Transformation of carbohydrates * Synthesis of cholesterol, ...

cardiomyocytes Cardiac muscle (also called heart muscle, myocardium, cardiomyocytes and cardiac myocytes) is one of three types of vertebrate muscle tissues, with the other two being skeletal muscle and smooth muscle. It is an involuntary, striated muscle tha ...

, and

macrophages Macrophages (abbreviated as M φ, MΦ or MP) ( el, large eaters, from Greek ''μακρός'' (') = large, ''φαγεῖν'' (') = to eat) are a type of white blood cell of the immune system that engulfs and digests pathogens, such as cancer ce ...

. However, until recently, it was unknown exactly how attachment and entry into these cells was achieved. Research has shown that PCV utilizes

clathrin-mediated endocytosis Receptor-mediated endocytosis (RME), also called clathrin-mediated endocytosis, is a process by which cells absorb metabolites, hormones, proteins – and in some cases viruses – by the inward budding of the plasma membrane (invagination). This ...

to enter the cell, though it's stipulated that there may still be other factors that haven't been identified. Once endocytosed, the

endosome Endosomes are a collection of intracellular sorting organelles in eukaryotic cells. They are parts of endocytic membrane transport pathway originating from the trans Golgi network. Molecules or ligands internalized from the plasma membrane can ...

and

lysosome A lysosome () is a membrane-bound organelle found in many animal cells. They are spherical vesicles that contain hydrolytic enzymes that can break down many kinds of biomolecules. A lysosome has a specific composition, of both its membrane pr ...

formation causes an acidic pH shift, which allows ATP-driven uncoating of the virus and allows it to escape the endosomes and lysosomes. After the virus escapes the endosomes and lysosomes, it travels to the nucleus through unknown means.

Escape

Besides ORF1 and ORF2, there is also an ORF3 which is not necessarily required for PCV to survive within the host. Research has shown that the protein coded in ORF3 can modulate the host cell's cell-division cycle and cause cell-mediated, virus-induced apoptosis. Using a

yeast two-hybrid screening Two-hybrid screening (originally known as yeast two-hybrid system or Y2H) is a molecular biology technique used to discover protein–protein interactions (PPIs) and protein–DNA interactions by testing for physical interactions (such as bindi ...

system of ORF3 against the porcine cDNA library indicated that the ORF3 protein interacts with the porcine pPirh2, which is an

E3 ubiquitin ligase A ubiquitin ligase (also called an E3 ubiquitin ligase) is a protein that recruits an E2 ubiquitin-conjugating enzyme that has been loaded with ubiquitin, recognizes a protein substrate, and assists or directly catalyzes the transfer of ubiquiti ...

. This E3 ubiquitin ligase normally interacts with

p53 p53, also known as Tumor protein P53, cellular tumor antigen p53 (UniProt name), or transformation-related protein 53 (TRP53) is a regulatory protein that is often mutated in human cancers. The p53 proteins (originally thought to be, and often s ...

during the cell division cycle and prevents it from halting the cell division cycle at

S-phase S phase (Synthesis Phase) is the phase of the cell cycle in which DNA is replicated, occurring between G1 phase and G2 phase. Since accurate duplication of the genome is critical to successful cell division, the processes that occur during ...

. However, ORF3 also interacts with pPirh2 at the same region as p53 and causes an upregulation of p53 expression. This increase in p53 stops the cell division cycle and the result of this is p53 mediated apoptosis, which releases PCV into the extracellular environment.

Contamination in human vaccine

On March 22, 2010, the U.S.

Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respon ...

(FDA) recommended suspending the use Rotarix, one of two vaccines licensed in the United States against

rotavirus ''Rotavirus'' is a genus of double-stranded RNA viruses in the family ''Reoviridae''. Rotaviruses are the most common cause of diarrhoeal disease among infants and young children. Nearly every child in the world is infected with a rotavirus ...

, due to findings of viral DNA contamination."Components of Extraneous Virus Detected in Rotarix Vaccine; No Known Safety Risk"
U.S.

, March 22, 2010 Follow-up work by GlaxoSmithKline confirmed the contamination in working cells and the viral "seed" used in Rotarix production, also confirming the material was likely present since the early stages of product development, including the

clinical trial Clinical trials are prospective biomedical or behavioral research studies on human participants designed to answer specific questions about biomedical or behavioral interventions, including new treatments (such as novel vaccines, drugs, diet ...

s for FDA approval."Detection of DNA from PCV1 in Rotarix"
FDA Testing of the other licensed vaccine against rotavirus infection, RotaTeq, also detected some components of both PCV-1 and PCV-2."DNA of Pig Viruses Found in Merck Vaccine"
''

The Wall Street Journal ''The Wall Street Journal'' is an American business-focused, international daily newspaper based in New York City, with international editions also available in Chinese and Japanese. The ''Journal'', along with its Asian editions, is published ...

'', May 7, 2010 Porcine circovirus 1 is not known to cause disease in humans or other animals. As of June 8, 2010, the FDA has, based on a careful review of a variety of scientific information, determined it is appropriate for clinicians and public health professionals in the United States to use both Rotarix and RotaTeq vaccine.

References

External links

The Control of Porcine Circovirus Diseases (PCVDs): Towards Improved Food Quality and SafetyAnimal Disease Diagnostic LaboratoryPorcine Circovirus Type 2 The Economics of PMWS - Porc Quebec Magazine ArticleStopcircovirus.comArticles by Quim Segalés on PCV2 - pig333.com
{{DEFAULTSORT:Porcine Circovirus Circoviridae Animal viral diseases Unaccepted virus taxa Swine diseases